Crystal of Thyroid Hormone B Receptor Agonist, Process for Preparing The Same and Use Thereof
20230357293 · 2023-11-09
Inventors
Cpc classification
C07F9/657181
CHEMISTRY; METALLURGY
A61K31/683
HUMAN NECESSITIES
A61K31/662
HUMAN NECESSITIES
International classification
Abstract
Disclosed are crystal of thyroid hormone β receptor agonist, process for preparing the same and use thereof. The crystal with basically no hygroscopicity, a relatively small crystal particle size and a relatively large drug specific surface area can improve the dissolution rate of drugs, is beneficial to the absorption of drugs and improves the bioavailability.
Claims
1. A crystal of a compound of formula I, having diffraction peaks at 20 angles using Cu-Kα radiation of 12.124±1, 15.483±1, 16.38±1, 16.666±1, 19.089±1, 20.415±1, and 20.821±1 in an X-ray power diffraction pattern, ##STR00003##
2. The crystal of claim 1, having diffraction peaks at 20 angles using Cu-Kα radiation of 7.951±1, 12.124±1, 13.555±1, 15.483±1, 16.017±1, 16.38±1, 16.666±1, 19.089±1, 20.415±1, 20.821±1, 21.764±1, 22.34±1, 22.628±1, 24.055±1, and 26.426±1 in an X-ray powder diffraction pattern.
3. The crystal of claim 1, having an endothermic peak at 111.92° C. when subject to thermal analysis using differential scanning calorimetry.
4. A process for preparing a crystal of claim 1, comprising (1) dissolving an amorphous compound of formula I in a first solvent to precipitate a solvate of the compound of formula I; and (2) dissolving the solvate obtained in step (1) in a second solvent, and pulping and/or crystallizing to obtain the crystal; wherein the first solvent is selected from the group consisting of C.sub.1-C.sub.4 lower alcohols; C.sub.3-C.sub.6 lower ketones; acetonitrile; methyl tert-butyl ether; diisopropyl ether; C.sub.5-C.sub.8 linear and branched alkanes; C.sub.5-C.sub.8 cycloalkanes; and a mixture of any two or more thereof; and wherein the second solvent is selected from the group consisting of C.sub.1-C.sub.4 lower alcohols; C.sub.3-C.sub.6 lower ketones; and a mixture of any two or more thereof.
5. A process for preparing a crystal of claim 1, comprising: (1) dissolving an amorphous compound of formula I in a first solvent to precipitate a solvate of the compound of formula I; and (2) pulping the solvate obtained in step (1) to obtain the crystal; wherein the first solvent is selected from the group consisting of C.sub.1-C.sub.4 lower alcohols; C.sub.3-C.sub.6 lower ketones; acetonitrile; methyl tert-butyl ether; diisopropyl ether; C.sub.5-C.sub.8 linear and branched alkanes; C.sub.5-C.sub.8 cycloalkanes; and a mixture of any two or more thereof.
6. The process of claim 4, wherein the pulping and/or crystallizing is carried out in a third solvent.
7. The process of claim 4, wherein the pulping is carried out under negative pressure and/or stirring, and/or the crystallizing is carried out under stirring.
8. The process of claim 4, wherein concentration is carried out under reduced pressure before the crystallizing.
9. A pharmaceutical composition comprising the crystal of claim 1, and optionally a pharmaceutically acceptable excipient.
10. (canceled)
11. A method for treating non-alcoholic steatohepatitis, comprising administering to a subject in need thereof a therapeutically effective amount of the crystal of claim 1.
12. The crystal of claim 1, having an X-ray powder diffraction pattern at 20 angles using Cu-Kα radiation as shown in
13. The process of claim 4, wherein the first solvent is selected from the group consisting of methyl tert-butyl ether, ethanol, and a mixture thereof.
14. The process of claim 4, wherein the second solvent is selected from the group consisting of methanol, ethanol, acetone, isopropanol, and a mixture of any two or more thereof.
15. The process of claim 5, wherein the first solvent is selected from the group consisting of methyl tert-butyl ether, ethanol, and a mixture thereof.
16. The process of claim 6, wherein the third solvent is selected from the group consisting of water, ethanol, and a mixture thereof.
17. The process of claim 5, wherein the pulping and/or crystallizing is carried out in a third solvent.
18. The process of claim 17, wherein the third solvent is selected from the group consisting of water, ethanol, and a mixture thereof.
19. The process of claim 5, wherein the pulping is carried out under negative pressure and/or stirring, and/or the crystallizing is carried out under stirring.
20. The process of claim 5, wherein concentration is carried out under reduced pressure before the crystallizing.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Specific embodiments of the disclosure are illustrated in conjunction with the following drawings:
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[0024]
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[0027]
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[0029]
DETAILED DESCRIPTION
[0030] The present disclosure will be further described below with reference to the embodiments. It should be noted that the following examples are merely illustrative and are not intended to limit the present disclosure. Various changes made by those skilled in the art according to the teachings of the present disclosure shall fall within the scope sought protection in the claims of the present disclosure.
[0031] The differential scanning calorimetry (DSC) conditions of the crystal form I of the compound of formula I used in the present disclosure are: heating rate: 10° C./min; heating range: 0-300° C.; pressure: 1013 Mbar; pressure rise rate: left: 20 mL/min, right: 100 mL/min. The used instrument is differential scanning calorimeter/DSC1.
[0032] The X-ray power diffraction (XRPD) pattern of the crystal form I of the compound of formula I of the present disclosure is tested on X-ray powder diffraction/D8 ADVANCE. X-ray source: Cu; voltage: 40 KV; current: 40 mA; scanning range: 3-40°; step length of scanning: 0.02°; and the retention time of each step: 0.1 s.
[0033] The infrared absorption spectrum conditions of the crystal form I of the compound of formula I used in the present disclosure are: instrument model: Frontier Fourier transform infrared spectrometer (FX057); potassium bromide tablet; wavelength interval: 400-4000 cm.sup.−1; and resolution: 4.0 cm.sup.−1.
[0034] The ultraviolet absorption spectrum conditions of the crystal form I of the compound of formula I used in the present disclosure are: instrument model: Lambda 365 Ultraviolet visible spectrophotometer (FX058); wavelength interval: 200-800 cm.sup.−1; scanning speed: 480 nm/min; slit width: 2 nm; and light speed mode: double light speed.
[0035] The Raman spectrum conditions of the crystal form I of the compound of formula I used in the present disclosure are: instrument model: DXR2xi dispersive laser confocal micro-Raman spectrometer; and excitation wavelength: 532 nm.
[0036] The thermogravimetric analysis (TGA) conditions of the crystal form I of the compound of formula I used in the present disclosure are: instrument name/model: thermogravimetric analyzer/TGA/DSC 2; heating range: 25-500° C. heating rate: 10° C./min; pressure: 1013 Mbar; and pressure rise rate: 20 mL/min.
[0037] The particle size conditions of the crystal form I of the compound of formula I used in the present disclosure are: name/model of detection instrument: micrometer particle size analyzer/MS3000; test method: dry method; sample injection rate: 50%; air pressure: 2.5 bar; slit width: 2.0 mm; refractive index: 1.52; absorption rate: 0.1; shade degree: 0.5% to 6%; background measurement time: 10 s; and sample measurement time: 10 s.
Example 1: Preparation of Crystal Form I of Compound of Formula I
[0038] 10 g of the amorphous sample of the compound of formula I was taken, dissolved at room temperature in 100 mL of methyl tert-butyl ether (MTBE), stirred for 5 h, filtered and dried to obtain the MTBE solvate of the compound of formula I for subsequent experiments.
[0039] 8 g of MTBE solvate of the compound of formula I was weighed, dissolved with absolute ethyl alcohol and concentrated under reduced pressure to about 24 g at 25 to 35° C. The resultant was transferred to a 250 mL single-port eggplant bottle. 16 to 20 mL of water was dropwise added while stirring. After dropwise addition, the resultant was stirred under negative pressure for 1 to 2 hours. After solid was precipitated, about 100 mL of water was dropwise added. The resultant was stirred at negative pressure for 12 to 20 hours, filtered and dried to obtain the crystal form I of the compound of formula I of the present disclosure. The production was 7.12 g and the yield was 89.0%.
[0040] The measured melting point of the crystal form I was 107.2 to 109.7° C.
TABLE-US-00002 TABLE 2 Data of Powder Diffraction of Crystal Form I Diffraction Angles 2θ (°) Spacing d (Å) Intensity 7.951 11.10997 16.4% 12.124 7.29432 100.0% 13.028 6.79017 7.7% 13.555 6.52728 11.5% 15.483 5.71856 35.0% 16.017 5.52886 18.1% 16.38 5.40732 56.4% 16.666 5.31514 38.2% 18.757 4.72694 9.9% 19.089 4.64553 33.5% 19.723 4.49769 8.4% 20.415 4.3467 34.9% 20.821 4.26285 41.0% 21.764 4.0802 15.4% 22.34 3.97631 11.4% 22.628 3.92647 11.5% 23.863 3.72596 7.9% 24.055 3.69653 16.8% 24.472 3.6346 7.6% 24.607 3.61485 8.6% 24.956 3.56512 7.0% 26.426 3.37005 11.0% 26.832 3.31992 4.1% 28.388 3.14142 4.8%
TABLE-US-00003 TABLE 3 Infrared Absorption Spectrum Attribution of Crystal Form I Absorption Intensity of Peak Absorption Vibration (cm.sup.−1) Peak Types Groups 3351.13 Strong νO—H hydroxyl-OH 1236.45 Strong νC—O CO 1080.99 Strong δC—O 2966.55 Strong νC—H Ar—H 2869.14 Medium νC—H —CH2 1080.99 Strong νP—O—C P—O—C 1051.55 Strong (fatty group) 1603.97 Medium νC—C Benzene skeleton 1513.33 Medium vibration 1482.65 Medium 1431.28 Medium 1236.46 Medium νC—O ethers-C—O—C
TABLE-US-00004 TABLE 4 Absorption Peak and Analysis of Ultraviolet Spectrum of Crystal form I Maximum Absorption Absorption Band Sort of Solvent Wavelength (nm) Attribution methanol 280.9 benzene B-band
Example 2: Preparation of Crystal Form I of Compound of Formula I
[0041] 8 g of MTBE solvate of the compound of formula I obtained in Example 1 was weighed, pulped for 20 hours with a mixed solution of 8 mL of absolute ethyl alcohol and 80 mL of water, filtered and dried to obtain a product, which was the crystal form I after test. The production was 7.20 g and the yield was 90.0%.
Example 3: Preparation of Crystal Form I of Compound of Formula I
[0042] 8 g of MTBE solvate of the compound of formula I obtained in Example 1 was weighed, dissolved with absolute ethyl alcohol, concentrated under reduced pressure at 25 to 35° C. to obtain about 24 g of resultant. The resultant was transferred to 250 mL of a single-port eggplant bottle. 16 to 20 mL of water was dropwise added while stirring. After dropwise addition, the resultant was stirred for 1 to 2 hours to precipitate a lot of solids. 100 mL of water was added, stirred for 10 to 20 hours, filtered and dried to obtain a product, which was the crystal form I after test. The production was 7.25 g and the yield was 90.6%.
Example 4: Preparation of Crystal Form I of Compound of Formula I
[0043] 8 g of the MTBE solvate of the compound of formula I obtained in Example 1 was weighed, dissolved with absolute ethyl alcohol and concentrated under reduced pressure at 25 to 35° C. to obtain about 24 g of resultant. The resultant was transferred into a dropping funnel. The resultant was dropwise added to a single-neck flask containing 100 mL of water. After dropwise addition, the resultant was continuously stirred for 12 to 20 hours, filtered and dried to obtain a product, which was the crystal form I after test. The production was 6.9 g and the yield was 86.3%.
Example 5: Preparation of Crystal Form I of Compound of Formula I
[0044] About 6 g of MTBE solvate of the compound of formula I obtained in Example 1 was weighed, dissolved with 50 to 60 mL of ethanol and concentrated to dryness under reduced pressure. 10 mL of ethanol was added and stirred for about 30 minutes to precipitate a solid. To the solid was added 30 mL of water, stirred for 30 to 60 minutes, supplemented with water for 30 min. The resultant was stirred overnight at room temperature, filtered, washed and dried to obtain a product, which was the crystal form I after test. The production was 4.98 g and the yield was 83.0%.
Example 6: Preparation of Crystal Form I of Compound of Formula I
[0045] About 3.71 g of MTBE solvate of the compound of formula I obtained in Example 1 was weighed, pulped for about 1 hour with a mixture of 20 mL of water and 10 mL of absolute ethyl alcohol under negative pressure. 10 mL of water was added and continuously stirred under negative pressure for 1 hour. About 60 mL of water was added. The resultant was stirred overnight at room temperature and normal pressure, filtered, washed and dried to obtain a product, which was the crystal form I after test. The production was 3.23 g and the yield was 87.1%.
Example 7: Preparation of Crystal Form I of Compound of Formula I
[0046] About 2 g of MTBE solvate of the compound of formula I obtained in Example 1 was weighed and dissolved with 4 mL of absolute ethyl alcohol. To the resultant mixture was added 1.5 mL of water and stirred at room temperature. 0.5 mL of water was added after 1 hour and continuously stirred for 1 hour. A solid was precipitated. 20 mL of water was added and continuously stirred for 12 to 20 hours. The resultant was filtered, washed and dried to obtain a product, which was the crystal form I after test. The production was 1.73 g and the yield was 86.6%.
Example 8: Preparation of Crystal Form I of Compound of Formula I
[0047] About 0.5 g of MTBE solvate of the compound of formula I obtained in Example 1 was weighed and dissolved with 2.5 mL of absolute ethyl alcohol. 47.5 mL of water was added and pulped and stirred for 12 to 20 hours. The resultant was filtered, washed and dried to obtain a product, which was the crystal form I after test. The production was 0.41 g and the yield was 82.0%.
Example 9: Preparation of Crystal Form I of Compound of Formula I
[0048] About 3 g of MTBE solvate of the compound of formula I obtained in Example 1 was weighed and dissolved with 20 to 30 mL of ethanol. The resultant mixture was concentrated to dryness under reduced pressure. 6 mL of ethanol was added and stirred for about 30 min. A solid was precipitated. The solid was taken out and dissolved with 4 mL of ethanol. 25 mL of water was added and pulped for 20 hours. The resultant was filtered, washed and dried to obtain a product, which was the crystal form I after test. The production was 2.6 g and the yield was 86.7%.
Example 10: Preparation of Crystal Form I of Compound of Formula I
[0049] 1 g of MTBE solvate of the compound of formula I obtained in Example 1 was weighed and dissolved with 20 to 30 mL of methanol. The resultant mixture was concentrated to dryness under reduced pressure. The solid was dissolved with about 2 to 3 mL of methanol. About 1 mL of water was added for crystallization. After dropwise addition, the mixture was stirred for 1 hour. 1 mL of water was dropwise added subsequently and stirred for 1 hour. 10 mL of water was added and stirred overnight at room temperature. The resultant was filtered, washed and dried to obtain a product, which was the crystal form I after test. The production was 0.7 g and the yield was 70.0%.
Example 11: Preparation of Crystal Form I of Compound of Formula I
[0050] 1 g of MTBE solvate of the compound of formula I obtained in Example 1 was weighed and dissolved with about 20 mL of acetone. The resultant mixture was concentrated to dryness under reduced pressure. The solid was dissolved with about 6 mL of acetone. 4 mL of water was dropwise added and stirred for about 30 min to precipitate and filter to obtain a solid. The solid was dissolved with 4 mL of ethanol. 4 mL of water was added and pulped and stirred for 1 hour. 20 mL of water was supplemented and stirred for 12 to 20 hours. The product was the crystal form I after test. The production was 0.81 g and the yield was 81.0%.
Example 12: Preparation of Crystal Form I of Compound of Formula I
[0051] 3 g of MTBE solvate of the compound of formula I obtained in Example 1 was weighed and dissolved with 30 mL of isopropanol. The resultant mixture was concentrated to dryness under reduced pressure. 10 mL of isopropanol was added and about 4 mL of water was dropwise added for crystallization. After dropwise addition, stirring was continuously carried out for 1 hour. 20 mL of water was added and pulped for 12 to 20 hours. A solid was obtained after filtering. The solid was dissolved with 6 mL of ethanol. 40 mL of water was added and pulped for 12 to 20 hours. The resultant was filtered, washed and dried to obtain a product, which was the crystal form I after test. The production was 2.3 g and the yield was 77.0%.
Example 13: Preparation of Crystal Form I of Compound of Formula I
[0052] 10 g of an amorphous sample of the compound of formula I was dissolved in 30 mL of ethanol. The resultant mixture was stirred at room temperature for 12 hours to precipitate a solid. An EtOH solvate of the compound of formula I was obtained.
[0053] About 5 g of EtOH solvate of the compound of formula I was weighed and pulped with 40 ml of water under negative pressure at room temperature. 5 ml of water was added every 2 hours. In accordance with decreasing trend of water and stirring conditions, an appropriate amount of water was added and stirred for about 6 to 7 hours. The resultant was filtered and washed with water to obtain a solid. The solid was dissolved with 40 mL of water and 4 mL of absolute ethyl alcohol. The mixture was stirred overnight at room temperature and normal pressure. The resultant was filtered, washed and dried to obtain a product, which was the crystal form I after test. The production was 4.3 g and the yield was 86.0%.
Example 14: Particle Size Test of Crystal Form I of Compound of Formula I
[0054] The crystal obtained in Example 1 was subject to a particle size test in accordance with the above conditions. The results were shown in Table 5.
TABLE-US-00005 TABLE 5 Particle Size Analysis of Crystal Form I Specific Area Dv Dv Dv Dv Test Sample (m.sup.2/kg) (10 μM) (50 μM) (90 μM) (95 μM) Example 1 807.1 6.41 20.30 48.23 59.10
[0055]
Example 15: Hygroscopicity Test of Crystal Form I of Compound of Formula I
[0056] About 28 mg of the crystal obtained in Example 1 was taken. The hygroscopicity of the crystal was determined with dynamic moisture adsorption instrument in accordance with the above conditions. The results were shown in Table 6.
TABLE-US-00006 TABLE 6 Hygroscopicity Analysis of Crystal Form I Test Sample Weight gain percentage at 80% relative humidity Example 1 0.1213%
[0057] The DVS diagram of the crystal obtained in Example 1 was shown in
Comparative Example 1: Preparation of Other Crystal Forms of Compound of Formula I
[0058] 1 g of MTBE solvate of the compound of formula I obtained in Example 1 was weighed and dissolved with 30 mL of n-heptane. The resultant mixture was concentrated under reduced pressure. About 1 mL of water was added for crystallization. After dropwise addition of water, stirring was carried out for 1 hour. 1 mL of water was continuously dropwise added. Stirring was carried out for 1 hour. 10 mL of water was supplemented. Stirring was carried out overnight at room temperature. No crystal of the compound of formula I was obtained by the process after test.
[0059] Although the present disclosure has been described to a certain extent, it is obvious that appropriate modifications in various conditions may be made without departing from the spirit and scope of the disclosure. It should be understood that the disclosure is not limited to the described embodiments, but is attributed to the scope of 10 the claims, which includes the equivalent substitutions for each factor.